Examining the Feasibility of Using Free Energy Perturbation (FEP+) in Predicting Protein Stability

The importance of engineering protein stability is well-known and has the potential to impact many fields ranging from pharmaceuticals to food sciences. Engineering proteins can be both a time-consuming and expensive experimental process. The use of computation is a potential solution to mitigating some of the time and expenses required to engineer a protein. This process has been previously hindered by inaccurate force fields or energy equations and slow computational processors; however, improved software and hardware have made this goal much more attainable. Here we find that Schrödinger's new FEP+, although still imperfect, proves more successful in predicting protein stability than other simpler methods of investigation. This increased accuracy comes at a cost of computational time and resources when compared to simpler methods. This work adds to the initial testing of FEP+ by offering options for more accurately predicting protein stability in an efficient manner.

[1]  Bernhard Rupp,et al.  Protein stability: a crystallographer’s perspective , 2016, Acta crystallographica. Section F, Structural biology communications.

[2]  F. Arnold,et al.  Protein stability promotes evolvability. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[3]  David A. Pearlman,et al.  A Comparison of Alternative Approaches to Free Energy Calculations , 1994 .

[4]  B. Berne,et al.  Replica exchange with solute tempering: a method for sampling biological systems in explicit water. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[5]  Herman van Vlijmen,et al.  Collaborating to improve the use of free-energy and other quantitative methods in drug discovery , 2016, Journal of Computer-Aided Molecular Design.

[6]  W. J. Becktel,et al.  Protein stability curves , 1987, Biopolymers.

[7]  Lei Jia,et al.  Structure Based Thermostability Prediction Models for Protein Single Point Mutations with Machine Learning Tools , 2015, PloS one.

[8]  Akinori Sarai,et al.  ProTherm: Thermodynamic Database for Proteins and Mutants , 1999, Nucleic Acids Res..

[9]  Yuji Sugita,et al.  How can free energy component analysis explain the difference in protein stability caused by amino acid substitutions? Effect of three hydrophobic mutations at the 56th residue on the stability of human lysozyme. , 2003, Protein engineering.

[10]  Peter A. Kollman,et al.  FREE ENERGY CALCULATIONS : APPLICATIONS TO CHEMICAL AND BIOCHEMICAL PHENOMENA , 1993 .

[11]  P. Kollman,et al.  Exhaustive mutagenesis in silico: Multicoordinate free energy calculations on proteins and peptides , 2000, Proteins.

[12]  M. Karplus,et al.  Dynamics of folded proteins , 1977, Nature.

[13]  Anthony Ivetac,et al.  High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875 , 2014, Nature.

[14]  Jennifer L. Knight,et al.  Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of a modern free-energy calculation protocol and force field. , 2015, Journal of the American Chemical Society.

[15]  Woody Sherman,et al.  Predicting Binding Affinities for GPCR Ligands Using Free-Energy Perturbation , 2016, ACS omega.

[16]  Charles H. Bennett,et al.  Efficient estimation of free energy differences from Monte Carlo data , 1976 .

[17]  Lingle Wang,et al.  On achieving high accuracy and reliability in the calculation of relative protein–ligand binding affinities , 2012, Proceedings of the National Academy of Sciences.

[18]  Woody Sherman,et al.  Predicting the Effect of Amino Acid Single-Point Mutations on Protein Stability-Large-Scale Validation of MD-Based Relative Free Energy Calculations. , 2017, Journal of molecular biology.

[19]  Eric A. Althoff,et al.  De Novo Computational Design of Retro-Aldol Enzymes , 2008, Science.

[20]  Richard A. Friesner,et al.  Integrated Modeling Program, Applied Chemical Theory (IMPACT) , 2005, J. Comput. Chem..

[21]  Daniel Cappel,et al.  Relative Binding Free Energy Calculations Applied to Protein Homology Models , 2016, J. Chem. Inf. Model..

[22]  T. Straatsma,et al.  Separation‐shifted scaling, a new scaling method for Lennard‐Jones interactions in thermodynamic integration , 1994 .

[23]  Dale E Tronrud,et al.  Lessons from the lysozyme of phage T4 , 2010, Protein science : a publication of the Protein Society.

[24]  T. N. Bhat,et al.  The Protein Data Bank , 2000, Nucleic Acids Res..

[25]  F. Arnold,et al.  Directed evolution of a thermostable esterase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[26]  Dong-Hoon Kim,et al.  Hydrogenases for biological hydrogen production. , 2011, Bioresource technology.

[27]  Jennifer L. Knight,et al.  OPLS3: A Force Field Providing Broad Coverage of Drug-like Small Molecules and Proteins. , 2016, Journal of chemical theory and computation.

[28]  Thomas Simonson,et al.  Free energy of particle insertion , 1993 .

[29]  Hege S. Beard,et al.  Applying Physics-Based Scoring to Calculate Free Energies of Binding for Single Amino Acid Mutations in Protein-Protein Complexes , 2013, PloS one.

[30]  T. Halgren.  Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94 , 1996, J. Comput. Chem..

[31]  W. L. Jorgensen,et al.  Monte Carlo simulation of differences in free energies of hydration , 1985 .

[32]  William L. Jorgensen,et al.  Improved convergence of binding affinities with free energy perturbation: Application to nonpeptide ligands with pp60src SH2 domain , 2001, J. Comput. Aided Mol. Des..

[33]  William L Jorgensen,et al.  Perspective on Free-Energy Perturbation Calculations for Chemical Equilibria. , 2008, Journal of chemical theory and computation.

[34]  Bert L de Groot,et al.  Protein thermostability calculations using alchemical free energy simulations. , 2010, Biophysical journal.

[35]  Robert Abel,et al.  Docking and free energy perturbation studies of ligand binding in the kappa opioid receptor. , 2015, The journal of physical chemistry. B.

[36]  J. Andrew McCammon,et al.  Dynamics and design of enzymes and inhibitors , 1986 .

[37]  Eric A. Althoff,et al.  Kemp elimination catalysts by computational enzyme design , 2008, Nature.

[38]  Hein J. Wijma,et al.  Computationally designed libraries for rapid enzyme stabilization , 2014, Protein engineering, design & selection : PEDS.

[39]  B. Matthews,et al.  Studies on protein stability with T4 lysozyme. , 1995, Advances in protein chemistry.

[40]  Ali Jazayeri,et al.  Structure of class B GPCR corticotropin-releasing factor receptor 1 , 2013, Nature.

[41]  R. Doolittle,et al.  A simple method for displaying the hydropathic character of a protein. , 1982, Journal of molecular biology.

[42]  Laura Pérez-Benito,et al.  Application of Free Energy Perturbation for the Design of BACE1 Inhibitors , 2016, J. Chem. Inf. Model..

[43]  W. Sherman,et al.  Prediction of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation and the OPLS Force Field. , 2010, Journal of chemical theory and computation.

[44]  V. Gapsys,et al.  Accurate and Rigorous Prediction of the Changes in Protein Free Energies in a Large‐Scale Mutation Scan , 2016, Angewandte Chemie.

[45]  Robert Abel,et al.  Sensitivity in binding free energies due to protein reorganization , 2016, bioRxiv.

[46]  Peter A. Kollman,et al.  Free energy calculations on protein stability: Thr-157 .fwdarw. Val-157 mutation of T4 lysozyme , 1989 .

[47]  A. Mark,et al.  Avoiding singularities and numerical instabilities in free energy calculations based on molecular simulations , 1994 .